U.S. patent application number 17/429183 was filed with the patent office on 2022-06-23 for process of making 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof.
The applicant listed for this patent is Nogra Pharma Limited. Invention is credited to Salvatore Demartis, Marie McNulty, Francesca Viti.
Application Number | 20220194894 17/429183 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-23 |
United States Patent
Application |
20220194894 |
Kind Code |
A1 |
Demartis; Salvatore ; et
al. |
June 23, 2022 |
PROCESS OF MAKING 3-(4'-AMINOPHENYL)-2-METHOXYPROPIONIC ACID, AND
ANALOGS AND INTERMEDIATES THEREOF
Abstract
The disclosure provides a process for the preparation of
3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and
intermediates thereof, contemplated to be capable of modulating the
activity of receptors, e.g., PPARs receptors.
Inventors: |
Demartis; Salvatore; (Milan,
IT) ; Viti; Francesca; (Salorino, CH) ;
McNulty; Marie; (Dublin, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nogra Pharma Limited |
Dublin 2 |
|
IE |
|
|
Appl. No.: |
17/429183 |
Filed: |
February 10, 2020 |
PCT Filed: |
February 10, 2020 |
PCT NO: |
PCT/EP2020/053369 |
371 Date: |
August 6, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62802802 |
Feb 8, 2019 |
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International
Class: |
C07C 231/02 20060101
C07C231/02; C07C 201/12 20060101 C07C201/12; C07C 205/56 20060101
C07C205/56; C07C 233/54 20060101 C07C233/54 |
Claims
1. A process for preparing a substantially optically pure compound
of Formula (VII): ##STR00051## the process comprising: reacting a
compound of Formula (I): ##STR00052## with an activating agent, in
the optional presence of a base, to form an intermediate of Formula
(I-A): ##STR00053## wherein LG is a leaving group; treating the
intermediate of Formula (I-A) with a base solution in the presence
of an alcohol solvent, to eliminate the leaving group and thereby
forming an intermediate of Formula (I-B): ##STR00054## hydrolyzing
the intermediate of Formula (I-B) to form a compound of Formula
(IV): ##STR00055## hydrogenating the compound of Formula (IV) to
form a compound of Formula (V): ##STR00056## resolving the compound
of Formula (V) to form a substantially optically pure compound of
Formula (VI): ##STR00057## and acylating the compound of Formula
(VI) to form the compound of Formula (VII).
2. The process of claim 1, wherein reacting a compound of Formula
(I) with an activating agent comprises reacting in the presence of
a base and a solvent.
3. The process of claim 2, wherein the solvent is selected from the
group consisting of toluene, dichloromethane, tetrahydrofuran,
diethyl ether, 2-methyltetrahydrofuran, and acetonitrile.
4. The process of claim 2 or 3, wherein the solvent is toluene.
5. The process of any one of claims 1-4, wherein the base is an
amine base.
6. The process of claim 5, wherein the amine base is selected from
the group consisting of triethylamine, N,N-diisopropylethylamine,
and pyridine.
7. The process of any one of claims 5-6, wherein the amine base is
triethylamine.
8. The process of any one of claims 1-7, wherein the activating
agent is a sulfonylating agent, or a halogenating agent.
9. The process of any one of claims 1-8 wherein the activating
agent is selected from the group consisting of a methanesulfonyl
chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl
chloride, phenyl triflimide, triflic anhydride, and
nonafluorobutanesulfonic anhydride.
10. The process of any one of claims 1-9, wherein the activating
agent is methanesulfonyl chloride.
11. The process of any one of claims 1-7, wherein the leaving group
is selected from the group consisting of --OSO.sub.2-aryl,
--OSO.sub.2--C.sub.1-4alkyl, chloro, bromo, and iodo; wherein
C.sub.1-4alkyl and aryl may be optionally substituted with one or
more substituents each independently selected, for each occurrence,
from the group consisting of fluoro, bromo, and --CH.sub.3.
13. The process of any one of claims 11 or 12, wherein the leaving
group is independently selected from the group consisting of:
--OSO.sub.2Me, ##STR00058## --OSO.sub.2CF.sub.3 ##STR00059## and
--OSO.sub.2CF.sub.2CF.sub.2CF.sub.2CF.sub.3.
14. The process of any one of claims 1-13, wherein the leaving
group is --OSO.sub.2Me.
15. The process of any one of claims 1-14 wherein the alcohol
solvent comprises at least one of methanol, ethanol, isopropanol,
and butanol.
16. The process of claim 15, wherein the alcohol solvent ccomprises
methanol.
17. The process of any one of claims 1-16, wherein the base
solution, comprises at least one of: sodium hydroxide, lithium
hydroxide, and potassium hydroxide.
18. The process of claim 17, wherein the base solution comprises
sodium hydroxide.
19. The process of any one of claims 1-18, wherein the base
solution comprises about 30% sodium hydroxide.
20. The process of any one of claims 1-19 wherein hydrolyzing the
intermediate of Formula (I-B) to form a compound of Formula (IV)
comprises: (i) contacting the intermediate of Formula (I-B) with an
alkali hydroxide and water; and (ii) neutralizing to form the
compound of Formula (IV).
21. The process of claim 20, wherein the alkali hydroxide is sodium
hydroxide.
22. The process of claim 20 or 21, wherein neutralizing comprises
acidifying to a pH of less than or equal to 3 by adding an
acid.
23. The process of claim 22, wherein the acid is phosphoric
acid.
24. The process of any one of claims 1-23 wherein, hydrogenating
the compound of Formula (IV) to form a compound of Formula (V)
comprises contacting the compound of Formula (IV) with hydrogen and
a catalyst.
25. The process of claim 24, wherein the catalyst is about 5%
Pd/C.
26. The process of any one of claims 1-25, wherein hydrogenating is
performed at a reaction temperature which is maintained between
about 60-80.degree. C. and at a pressure between about 3 to 5
atm.
27. The process of any one of claims 1-26, wherein resolving the
compound of Formula (V) to form a substantially optically pure
compound of Formula (VI) comprises: c) resolving a compound of
Formula (V) in the presence of a chiral acid thereby forming a
chiral salt of the compound of Formula (VI): d) neutralizing the
chiral salt of the compound of Formula (VI) thereby forming the
compound of Formula (VI).
28. The process of claim 27, wherein the chiral acid is selected
from the group consisting of (S)-(+)-camphor-10-sulfonic acid,
(2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid, and (R)-(-)-mandelic
acid or an enantiomer thereof.
29. The process of claim 27 or 28, wherein the chiral acid is
(S)-(+)-camphor-10-sulfonic acid.
30. The process of any one of claims 27-29, wherein the chiral salt
of the compound of Formula (VI) is: ##STR00060##
(S)-(+)-camphor-10-sulfonic acid
31. The process of any one of claims 1-30, wherein resolving
further comprises adding a primer and maintaining a temperature
between 30-35.degree. C. while stirring.
32. The process of claim 31, wherein the primer consists of a
substantially optically pure chiral acid salt of the compound of
Formula (VI).
33. The process of claim 32, wherein the chiral acid is
(S)-(+)-camphor-10-sulfonic acid.
34. The process of any one of claims 27-33, wherein neutralizing
comprises contacting the chiral salt of the compound of Formula
(VI), with (i) and aqueous base; and then (ii) acicifying the
solution by adding an acid.
35. The process of claim 34, wherein the aqueous base comprises
aqueous ammonium hydroxide.
36. The process of claim 1-35, wherein acylating comprises
contacting the compound of Formula (VI) with an acylating agent in
the presence of an organic solvent selected from the group
consisting of ethyl acetate, tetrahydrofuran, diethyl ether,
dichloromethane, and toluene.
37. The process of claim 36, wherein acylating agent is acetic
anhydride.
38. The process of claim 36 or 37, wherein the organic solvent is
ethyl acetate.
39. The process of any one of claims 1-39, wherein acylating occurs
at a temperature between 60-70.degree. C.
40. The process of any one of claims 1-39, wherein the compound of
Formula (VII) is produced on a multi-kilogram scale.
41 The process of claim 40, wherein at least about 8 to 10 kg is
obtained.
42. The process of any one of claims 1-41, wherein the
substantially optically pure compound of Formula (VII) is not less
than 98%.
43. the purified compound of Formula (VII) of claim 42, wherein the
content of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid is not
more than 0.15% by HPLC.
44. A process for preparing a compound of Formula (I): ##STR00061##
the process comprising, providing a mixture of a compound of
Formula (II): ##STR00062## and a compound of Formula (III):
##STR00063## and contacting the mixture with a base; thereby
forming a compound of Formula (I).
45. The process of claim 44, wherein contacting occurs in a
solvent.
46. The process of claim 44 or 45, wherein the solvent is
tetrahydrofuran.
47. The process of any one of claims 44-46, wherein contacting is
performed at a temperature less than or equal to 10.degree. C.
48. The process of any one of claims 44-47, wherein contacting
comprises stirring for about 5 minutes and/or is performed at a
reaction temperature which is maintained between -10 to 10.degree.
C.
49. The process of any one of claims 44-48, wherein the base is an
alkali metal alkoxide.
50. The process of claim 49, wherein the alkali metal alkoxide is
selected from the group consisting of sodium methoxide, lithium
methoxide, and potassium methoide.
51. The process of any one of claims 49-50, wherein the alkali
metal alkoxide is sodium methoxide.
52. A compound represented by: ##STR00064## or a pharmaceutically
acceptable salt thereof.
Description
BACKGROUND
[0001] Peroxisome Proliferator Activated Receptors (PPARs) are
members of the nuclear hormone receptor super family, which are
ligand-activated transcription factors regulating gene expression.
Certain PPARs play roles in the regulation of cell differentiation,
development and metabolism of higher organisms.
[0002] Three types of PPAR have been identified: alpha, expressed
in the liver, kidney, heart and other tissues and organs,
beta/delta expressed, for example, in the brain, and gamma,
expressed in three forms: gamma1, gamma2, and gamma3. PPAR.gamma.
receptors have been associated with a number of disease states
including fibrotic diseases, dyslipidemia, hyperlipidemia,
hypercholesteremia, atherosclerosis, atherogenesis,
hypertriglyceridemia, heart failure, myocardial infarction,
vascular diseases, cardiovascular diseases, hypertension, obesity,
inflammation, arthritis, cancer, Alzheimer's disease, skin
disorders, respiratory diseases, ophthalmic disorders, IBDs
(irritable bowel disease), ulcerative colitis and Crohn's
disease.
[0003] Further, treatment of tumor cells with ligands of
PPAR.gamma. receptors can induce a decrease in cellular
proliferation, cell differentiation and apoptosis, and therefore
may be useful in preventing carcinogenesis. Intestinal
anti-inflammatory activity may be dependent on binding and
subsequent activation of PPAR.gamma. receptors.
[0004] Accordingly, effective processes for making compounds
capable of modulating the activity of PPARs receptors are needed to
address the treatment of such diseases.
SUMMARY
[0005] The disclosure provides, for example, a process for the
preparation of compounds which may be modulators of PPARs
receptors.
[0006] The present disclosure provides, in part, a process for the
preparation of a compound of Formula (VII):
##STR00001##
[0007] One embodiment provides a process for preparing of a
compound of Formula (VI):
##STR00002##
[0008] Also contemplated herein is a process for the preparation of
analogs and intermediates thereof.
[0009] In one embodiment, at least some of the compounds identified
as intermediates e.g., as part of a synthetic scheme disclosed
herein are contemplated as compounds of the disclosure, e.g., a
compound represented by Formula (I) or a pharmaceutically
acceptable salt or stereoisomer thereof:
##STR00003##
DETAILED DESCRIPTION
[0010] The features and other details of the disclosure will now be
more particularly described. Before further description of the
present disclosure, certain terms employed in the specification,
examples and appended claims are collected here. These definitions
should be read in light of the remainder of the disclosure and
understood as by a person of skill in the art. Unless defined
otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood by a person of ordinary skill
in the art.
DEFINITIONS
[0011] The term "alkenyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
double bond, such as a straight or branched group of 2-12, 2-10, or
2-6 carbon atoms, referred to herein as C.sub.2-C.sub.12alkenyl,
C.sub.2-C.sub.10alkenyl, and C.sub.2-C.sub.6alkenyl, respectively.
Exemplary alkenyl groups include, but are not limited to, vinyl,
allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,
hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,
4-(2-methyl-3-butene)-pentenyl, etc.
[0012] The term "alkoxy" as used herein refers to an alkyl group
attached to an oxygen (--O-alkyl). Exemplary alkoxy groups include,
but are not limited to, groups with an alkyl, alkenyl or alkynyl
group of 1-12, 1-8, or 1-6 carbon atoms, referred to herein as
C.sub.1-C.sub.12alkoxy, C.sub.1-C.sub.8alkoxy, and
C.sub.1-C.sub.6alkoxy, respectively. Exemplary alkoxy groups
include, but are not limited to methoxy, ethoxy, etc. Similarly,
exemplary "alkenoxy" groups include, but are not limited to
vinyloxy, allyloxy, butenoxy, etc.
[0013] The term "alkyl" as used herein refers to a saturated
straight or branched hydrocarbon, such as a straight or branched
group of 1-12, 1-10, 1-6, 1-4, or 1-3 carbon atoms, referred to
herein as C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.10alkyl,
C.sub.1-C.sub.6alkyl, C.sub.1-4alkyl, and C.sub.1-3alkyl
respectively. Exemplary alkyl groups include, but are not limited
to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,
2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl,
2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl,
3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,
3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl,
pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. In certain
embodiments, alkyl refers to C.sub.1-C.sub.6 alkyl. In certain
embodiments, cycloalkyl refers to C.sub.3-C.sub.6cycloalkyl.
[0014] Alkyl, alkenyl and alkynyl groups can, in some embodiments,
be optionally be substituted with or interrupted by at least one
group selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl,
amido, amidino, amino, aryl, arylalkyl, azido, carbamate,
carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino,
ketone, nitro, phosphate, phosphonato, phosphinato, sulfate,
sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0015] The term "alkynyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
triple bond, such as a straight or branched group of 2-12, 2-8, or
2-6 carbon atoms, referred to herein as C.sub.2-C.sub.12alkynyl,
C.sub.2-C.sub.8alkynyl, and C.sub.2-C.sub.6alkynyl, respectively.
Exemplary alkynyl groups include, but are not limited to, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl,
etc.
[0016] The term "amide" or "amido" as used herein refers to a
radical of the form --R.sub.aC(O)N(R.sub.b)--,
--R.sub.aC(O)N(R.sub.b)R.sub.c--, or --C(O)NR.sub.bR.sub.c, wherein
R.sub.a, R.sub.b and R.sub.c are each independently selected from
alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heteroaryl,
heterocyclyl, and hydrogen. The amide can be attached to another
group through the carbon, the nitrogen, R.sub.b, R.sub.c, or
R.sub.a. The amide also may be cyclic, for example R.sub.b and
R.sub.c, R.sub.a and R.sub.b, or R.sub.a and R.sub.c may be joined
to form a 3- to 12-membered ring, such as a 3- to 10-membered ring
or a 5- to 6-membered ring.
[0017] The term "amidino" as used herein refers to a radical of the
form --C(.dbd.NR)NR'R'' where R, R', and R'' can each independently
be selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloalkyl, heteroaryl, and heterocyclyl.
[0018] The term "amine" or "amino" as used herein refers to a
radical of the form --NR.sub.dR.sub.e, --N(R.sub.d)R.sub.e--, or
--R.sub.eN(R.sub.d)R.sub.f-- where R.sub.d, R.sub.e, and R.sub.f
are independently selected from alkyl, alkenyl, alkynyl, aryl,
arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and
hydrogen. The amino can be attached to the parent molecular group
through the nitrogen, R.sub.d, R.sub.e or R.sub.f. The amino also
may be cyclic, for example any two of R.sub.d, R.sub.e or R.sub.f
may be joined together or with the N to form a 3- to 12-membered
ring, e.g., morpholino or piperidinyl. The term amino also includes
the corresponding quaternary ammonium salt of any amino group,
e.g., --[N(R.sub.d)(R.sub.e)(R.sub.f)].sup.+. Exemplary amino
groups include aminoalkyl groups, wherein at least one of R.sub.d,
R.sub.e, or R.sub.f is an alkyl group.
[0019] The term "aryl" as used herein refers to a mono-, bi-, or
other multi-carbocyclic, aromatic ring system. In certain
embodiments, aryl refers to a monocyclic and/or bicyclic, 6 to 10
membered ring. The aromatic ring may be substituted at one or more
ring positions with substituents selected from alkanoyl, alkoxy,
alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl,
azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester,
ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,
hydroxyl, imino, ketone, nitro, phosphate, phosphonato,
phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and
thiocarbonyl. The term "aryl" also includes polycyclic ring systems
having two or more cyclic rings in which two or more carbons are
common to two adjoining rings (the rings are "fused rings") wherein
at least one of the rings is aromatic, e.g., the other cyclic rings
may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
Exemplary aryl groups include, but are not limited to, phenyl,
tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl.
[0020] The term "arylalkyl" as used herein refers to an aryl group
having at least one alkyl substituent, e.g., -aryl-alkyl. Exemplary
arylalkyl groups include, but are not limited to, arylalkyls having
a monocyclic aromatic ring system, wherein the ring comprises 6
carbon atoms. For example, "phenylalkyl" includes
phenylC.sub.4alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, etc.
[0021] The term "carbonyl" as used herein refers to the radical
--C(O)--.
[0022] The term "carboxy" as used herein refers to the radical
--COOH or its corresponding salts, e.g., --COONa, etc.
[0023] The term "cyano" as used herein refers to the radical
--CN.
[0024] The term "cycloalkyl" as used herein refers to a monovalent
saturated or unsaturated cyclic, bicyclic, or bridged bicyclic
hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to
herein, e.g., as "C.sub.4-8cycloalkyl," derived from a cycloalkane.
Exemplary cycloalkyl groups include, but are not limited to,
cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes,
cyclobutanes and cyclopropanes. Cycloalkyl groups may be
substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,
amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,
carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,
nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,
sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be
fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain
embodiments, cycloalkyl refers to C.sub.3-C.sub.6 alkyl.
[0025] The terms "halo" or "halogen" as used herein refer to F, Cl,
Br, or I.
[0026] The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms.
[0027] The term "nitro" as used herein refers to the radical
--NO.sub.2.
[0028] The term "phenyl" as used herein refers to a 6-membered
carbocyclic aromatic ring. The phenyl group can also be fused to a
cyclohexane or cyclopentane ring. Phenyl can be substituted with
one or more substituents including alkanoyl, alkoxy, alkyl,
alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,
carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate,
sulfide, sulfonamido, sulfonyl and thiocarbonyl.
[0029] The term "phosphate" as used herein refers to the radical
--OP(O)(OR.sub.aa).sub.2 or its anions. The term "phosphonate"
refers to the radical --P(O)(OR.sub.aa).sub.2 or its anions. The
term "phosphinate" refers to the radical --PR.sub.aa(O)(OR.sub.aa)
or its anion, where each R.sub.aa can be selected from, for
example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
[0030] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" as used herein refers to
any and all solvents, dispersion media, coatings, isotonic and
absorption delaying agents, and the like, that are compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
[0031] The term "pharmaceutical composition" as used herein refers
to a composition comprising at least one compound as disclosed
herein formulated together with one or more pharmaceutically
acceptable carriers.
[0032] The term "pharmaceutically acceptable salt(s)" as used
herein refers to salts of acidic or basic groups that may be
present in compounds used in the present compositions. Compounds
included in the present compositions that are basic in nature are
capable of forming a wide variety of salts with various inorganic
and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of such basic
compounds are those that form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, including but
not limited to malate, oxalate, chloride, bromide, iodide, nitrate,
sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate, citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present compositions that include an amino moiety
may form pharmaceutically acceptable salts with various amino
acids, in addition to the acids mentioned above. Compounds included
in the present compositions that are acidic in nature are capable
of forming base salts with various pharmacologically acceptable
cations. Examples of such salts include alkali metal or alkaline
earth metal salts and, particularly, calcium, magnesium, sodium,
lithium, zinc, potassium, and iron salts.
[0033] The compounds of the disclosure may contain one or more
stereogenic centers and/or double bonds and, therefore, exist as
stereoisomers, such as geometric isomers, enantiomers or
diastereomers. The term "stereoisomers" when used herein consist of
all geometric isomers, enantiomers or diastereomers. These
compounds may be designated by the symbols "R" or "S," depending on
the configuration of substituents around the stereogenic carbon
atom. The present disclosure encompasses various stereoisomers of
these compounds and mixtures thereof. Stereoisomers include
enantiomers and diastereomers. Mixtures of enantiomers or
diastereomers may be designated "(.+-.)" in nomenclature, but the
skilled artisan will recognize that a structure may denote a chiral
center implicitly.
[0034] Individual stereoisomers of compounds of the present
disclosure can be prepared synthetically from commercially
available starting materials that contain asymmetric or stereogenic
centers, or by preparation of racemic mixtures followed by
resolution methods well known to those of ordinary skill in the
art. These methods of resolution are exemplified by (1) attachment
of a mixture of enantiomers to a chiral auxiliary, separation of
the resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary, (2) salt formation employing an optically active
resolving agent, or (3) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns. Stereoisomeric
mixtures can also be resolved into their component stereoisomers by
well-known methods, such as chiral-phase gas chromatography,
chiral-phase high performance liquid chromatography, crystallizing
the compound as a chiral salt complex, or crystallizing the
compound in a chiral solvent. Stereoisomers can also be obtained
from stereomerically-pure intermediates, reagents, and catalysts by
well-known asymmetric synthetic methods.
[0035] Geometric isomers can also exist in the compounds of the
present disclosure. The symbol
denotes a bond that may be a single, double or triple bond as
described herein. The present disclosure encompasses the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond or
arrangement of substituents around a carbocyclic ring. Substituents
around a carbon-carbon double bond are designated as being in the
"Z" or "E" configuration wherein the terms "Z" and "E" are used in
accordance with IUPAC standards. Unless otherwise specified,
structures depicting double bonds encompass both the "E" and "Z"
isomers.
[0036] Substituents around a carbon-carbon double bond
alternatively can be referred to as "cis" or "trans," where "cis"
represents substituents on the same side of the double bond and
"trans" represents substituents on opposite sides of the double
bond. The arrangement of substituents around a carbocyclic ring are
designated as "cis" or "trans." The term "cis" represents
substituents on the same side of the plane of the ring and the term
"trans" represents substituents on opposite sides of the plane of
the ring. Mixtures of compounds wherein the substituents are
disposed on both the same and opposite sides of plane of the ring
are designated "cis/trans."
[0037] The term "substantially optically pure", "substantially
enantiomerically pure", "optically pure" or "enantiomerically pure"
as used herein when referring to a compound (e.g., a compound
described herein) means that at least 95%, for example, at least
96%, at least 97%, or at least 98% of the compound has the desired
stereogenic center in a given configuration. It will be appreciated
that the percentage is expressed as a percentage of both
enantiomers of the compound. For example, a compound of Formula VII
is substantially optically pure if, based on the total of both the
levorotatory and dextrorotatory enantiomers, at least 95% is
(S)--(-)-3-(4-acetamidophenyl)-2-methoxypropionic acid (the
levorotatory enantiomer).
[0038] The compounds disclosed herein can exist in solvated as well
as unsolvated forms with pharmaceutically acceptable solvents such
as water, ethanol, and the like, and it is intended that the
disclosure embrace both solvated and unsolvated forms. In some
embodiments, the compound is amorphous. In some embodiments, the
compound is in a crystalline form. In some embodiments, the
compound is a polymorph.
[0039] The disclosure also embraces isotopically labeled compounds
of the disclosure which are identical to those recited herein,
except that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the disclosure include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively.
[0040] Certain isotopically-labeled disclosed compounds (e.g.,
those labeled with .sup.3H and .sup.14C) are useful in compound
and/or substrate tissue distribution assays. Tritiated (i.e.,
.sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with heavier isotopes such as deuterium (i.e.,
.sup.2H) may afford certain therapeutic advantages resulting from
greater metabolic stability (e.g., increased in vivo half-life or
reduced dosage requirements) and hence may be preferred in some
circumstances. Isotopically labeled compounds of the disclosure can
generally be prepared by following procedures analogous to those
disclosed in the e.g., Examples herein by substituting an
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0041] The term "prodrug" refers to compounds that are transformed
in vivo to yield a disclosed compound or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. For example, if a compound of the disclosure
or a pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0042] Similarly, if a compound of the disclosure contains an
alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl, 1
-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N-(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and -aminoacyl, or .alpha.-aminoacyl-.alpha.-aminoacyl,
where each .alpha.-aminoacyl group is independently selected from
the naturally occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(.sub.c1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0043] If a compound of the disclosure incorporates an amine
functional group, a prodrug can be formed by the replacement of a
hydrogen atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY.sup.1
wherein Y.sup.1 is H, (C.sub.1-C.sub.6)alkyl or benzyl,
--C(OY.sup.2)Y.sup.3 wherein Y.sup.2 is (C.sub.2-C.sub.4) alkyl and
Y.sup.3 is (C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
[0044] The disclosure provides, at least in part, compounds
represented by Formula (I), Formula (IV), Formula (V), Formula
(VI), and Formula (VII), as depicted below. Also contemplated
herein are pharmaceutical compositions that include a compound
represented by Formula (I), Formula (IV), Formula (V), Formula
(VI), and Formula (VII), and e.g., a pharmaceutically acceptable
excipient and/or carrier.
Compounds
[0045] Provided herein in part is a process for preparing a
substantially optically pure compound of Formula (VII):
##STR00004##
[0046] the process comprising: [0047] reacting a compound of
Formula (I):
##STR00005##
[0047] with an activating agent, in the optional presence of a
base, to form an intermediate of Formula (I-A):
##STR00006##
wherein LG is a leaving group;
[0048] treating the intermediate of Formula (I-A) with a base
solution in the presence of an alcohol solvent, to eliminate the
leaving group and thereby forming an intermediate of Formula
(I-B):
##STR00007##
[0049] hydrolyzing the intermediate of Formula (I-B) to form a
compound of Formula (IV):
##STR00008##
[0050] hydrogenating the compound of Formula (IV) to form a
compound of Formula (V):
##STR00009##
[0051] optionally resolving the compound of Formula (V) to form a
substantially optically pure compound of Formula (VI):
##STR00010##
and acylating the compound of Formula (VI) to form the compound of
Formula (VII).
[0052] Reacting a compound of Formula (I) with an activating agent
may comprise reacting in the presence of a base and a solvent. In
some embodiments, the solvent is selected from the group consisting
of toluene, dichloromethane, tetrahydrofuran, diethyl ether,
2-methyltetrahydrofuran, and acetonitrile, for example, the solvent
may be toluene. The base may be an amine base, for example,
selected from the group consisting of triethylamine,
N,N-diisopropylethylamine, and pyridine. For example, the amine
base may be triethylamine.
[0053] The compound of Formula (I) can be an isolated solid prior
to this step or can be dissolved in an appropriate solvent, for
example, a solvent used in making or working up the compound of
Formula (I). For example, the compound of Formula (I) can be
unisolated and dissolved in an organic solvent, e.g., toluene,
prior to this step.
[0054] Contemplated activating agent includes a sulfonylating
agent, or a halogenating agent. For example, the activating agent
may be selected from the group consisting of a methanesulfonyl
chloride, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl
chloride, phenyl triflimide, triflic anhydride, and
nonafluorobutanesulfonic anhydride. In some embodiments, the
activating agent is methanesulfonyl chloride.
[0055] In some embodiments, the leaving group is selected from the
group consisting of --OSO.sub.2-aryl, --OSO.sub.2-C.sub.1-4alkyl,
chloro, bromo, and iodo; wherein C.sub.1-4alkyl and aryl may be
optionally substituted with one or more substituents each
independently selected, for each occurrence, from the group
consisting of fluoro, bromo, and --CH.sub.3. For example, the
leaving group may be --OSO.sub.2-phenyl or
--OSO.sub.2-C.sub.1-4alkyl.
[0056] In some embodiments, the leaving group is selected from the
group consisting of: --OSO.sub.2Me,
##STR00011##
--OSO.sub.2CF.sub.3,
##STR00012##
and --OSO.sub.2CF.sub.2CF.sub.2CF.sub.2CF.sub.3, e.g., the leaving
group may be --OSO.sub.2Me.
[0057] Contemplated alcohol solvents may include at least one of
methanol, ethanol, isopropanol, and butanol. For example, the
alcohol solvent may include methanol.
[0058] In some embodiments, the base solution, comprises at least
one of: sodium hydroxide, lithium hydroxide, and potassium
hydroxide. For example, a base solution may include sodium
hydroxide, for example, 30% sodium hydroxide.
[0059] In some embodiments, hydrolyzing the intermediate of Formula
(I-B) to form a compound of Formula (IV) comprises: contacting the
intermediate of Formula (I-B) with an alkali hydroxide (e.g.,
sodium hydroxide) and water; and neutralizing to form the compound
of Formula (IV). Neutralizing can include acidifying to a pH of
less than or equal to 3 by adding an acid, for example, phosphoric
acid or hydrochloric acid, or a mixture thereof.
[0060] In some embodiments, hydrogenating the compound of Formula
(IV) to form a compound of Formula (V) comprises contacting the
compound of Formula (IV) with hydrogen and a catalyst, for example,
a catalyst selected from the group consisting of PtO.sub.2,
Pd(OH).sub.2/C, Pt/C, 10% Pd/C, and 5% Pd/C, e.g., 5% Pd/C
catalyst. Hydrogenating may be performed at a reaction temperature
which is maintained between about 60-80.degree. C. and at a
pressure between about 3 to 5 atm, about 3.5 to 4.5 atm, or about
4.0 to 4.5 atm. For example, hydrogenating may be performed in the
presence of one or more hydrogenation solvents selected from the
group consisting of an aqueous ammonia solution, methanol, ethanol,
isopropanol, NN-dimethylformamide, tetrahydrofuran and ethyl
acetate, e.g., an aqueous ammonia solution, methanol, or
NN-dimethylformamide. In some embodiments the hydrogenation solvent
is methanol or a mixture of methanol and ammonia, e.g., a 30%
ammonia aqueous solution.
[0061] Following hydrogenation, the compound of Formula (V) may
optionally be isolated by contacting the solution with an acid, for
example, acetic acid or hydrochloric acid, or a mixture
thereof.
[0062] Resolving the compound of Formula (V) to form a
substantially optically pure compound of Formula (VI) may include:
[0063] a) resolving a compound of Formula (V) in the presence of a
chiral acid thereby forming a chiral salt of the compound of
Formula (VI); and [0064] b) neutralizing the chiral salt of the
compound of Formula (VI) thereby forming the compound of Formula
(VI).
[0065] In some embodiments, the chiral acid is selected from the
group consisting of (S)-(+)-camphor-10-sulfonic acid,
(2R,3R)-(+)-tartaric acid, (S)-(-)-malic acid,
(1S)-(+)-3-bromocamphor-10-sulfonic acid, (S)-1-phenylethane
sulphonic acid, dibenzoyl-L-tartaric acid, glutamic acid, (1R,
3S)-camphoric acid, (1S)-camphanic acid and (R)-(-)-mandelic acid
and all other chiral acids that can lead to resolution of racemic
mixture or an enantiomer thereof, e.g., (S)-(+)-camphor-10-sulfonic
acid.
[0066] In some embodiments, the chiral salt of the compound of
Formula (VI) is:
##STR00013##
[0067] In various embodiments, resolving may further comprise
adding a primer and maintaining a temperature between 30-35.degree.
C. while stirring, and/or may occur in the presence of acetone and
water. In some embodiments, resolving may further comprise
maintaining a temperature between 55-60.degree. C. (e.g.,
58.degree. C.) while stirring, and/or may occur in the presence of
acetone and water.
[0068] A primer may be a substantially optically pure chiral acid
salt of the compound of Formula (VI). In some embodiments, the
chiral acid is (S)-(+)-camphor-10-sulfonic acid.
[0069] For example, the primer may be represented by:
##STR00014##
[0070] At the end of resolving, if specifications are not met,
reprocessing can occur where the solution maintained at the
resolving temperature while stirring for a longer time.
[0071] Neutralizing may include contacting the chiral salt of the
compound of Formula (VI), with (i) an aqueous base (e.g., ammonium
hydroxide); and then (ii) acidifying the solution by adding an acid
(e.g., acetic acid). Neutralizing may occur in the presence of one
or more solvents, e.g., in the presence of water and ethyl
acetate.
[0072] Acylating may include contacting the compound of Formula
(VI) with an acylating agent (e.g., acetic anhydride) in the
presence of an organic solvent selected from the group consisting
of ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane,
and toluene, e.g., ethyl acetate. Such acylating may occur at a
temperature between 60 to 70.degree. C., for example, between 65 to
70.degree. C. Acylating may further comprise dissolving the
compound isolated from the previous step in one or more solvents,
e.g., water and/or ethyl acetate, to prepare a solution and
contacting the solution with an acylating agent, e.g., acetic acid.
Such step may occur at a temperature between 60 to 70.degree. C.,
for example, at a temperature between 65 to 70.degree. C.
[0073] In some embodiments, after optionally resolving the compound
of Formula (V) to form a substantially optically pure compound of
Formula (VI), a mother liquor derived from resolution step may
still contain the desired enantiomer (as a salt of the resolving
agent) together with the undesired one. In these embodiments,
resolving may optionally further comprise: [0074] a) recovering the
mixture of enantiomers (as chiral salts of the resolving agent)
from the mother liquor, neutralizing the chiral salts to form a
compound of Formula (V), and resolving the compound of Formula (V)
providing additional substantially optically pure compound of
Formula (VI), thereby increasing the total process yield; or [0075]
b) distilling part of the mother liquor and precipitating the
desired enantiomer as a salt of the chiral resolving agent from the
mother liquor, thereby increasing the total process yield.
[0076] Also contemplated herein is a process of racemizing the
undesired enantiomer or chiral salt thereof in the presence of a
base and resolving the resulting mixture of (R), and (S)
enantiomers using a resolution process contemplated herein to form
the desired enantiomer.
[0077] Contemplated bases include those selected from the group
consisting of hydroxides, alkoxides (e.g., methoxide), amides
(e.g., lithium diisopropylamide), hydrides (e.g., NaH),
organolithiums, and Grignard reagents. For bases that require a
counterion, exemplary counterions contemplated herein may include
alkali metals or alkaline earth metals e.g., lithium, sodium,
potassium, or calcium; or organic counterions e.g., tetraalkyl
ammoniums.
[0078] In some embodiments, the compound of Formula (VII) can be
produced on a multi-kilogram scale, for example, at least about 8
to 11 kg, about 13 to 15 kg, or about 130 to 150 kg is obtained. In
some embodiments, at least about 130 kg of the compound of Formula
(VII) is obtained.
[0079] In some embodiments, the substantially optically pure
compound of Formula (VII) is at least 98% of the desired
enantiomer:
##STR00015##
(expressed as a percentage of both enantiomers). In some
embodiments, the content of
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid may not, for
example, be more than 0.15% by HPLC.
[0080] In an alternative embodiment a disclosed preparation of a
substantially optically pure compound of Formula (VII) comprises
acylating racemic compound (V) yielding a racemic mixture of
3-(4-acetamidophenyl)-2-methoxypropionic acid, and resolving the
racemic 3-(4-cetamidophenyl)-2-methoxypropionic acid to provide
substantially enantiomerically pure compound of Formula (VII). For
example, forming substantially optically pure compound of Formula
(VII) may comprise: [0081] a) resolving a racemic mixture of
3-(4-acetamidophenyl)-2-methoxypropionic acid in the presence of a
chiral base thereby forming a chiral salt of the compound; and
[0082] b) neutralizing the chiral salt of the compound thereby
forming the compound of Formula (VII).
[0083] In some embodiments, the chiral base is selected from the
group consisting of e.g., enantiomerically pure 1-amino-2-propanol,
brucine, dehydroabietylamine, N,.alpha.-dimethylbenzylamine,
N,N-dimethyl-1 -phenylethylamine, ephedrine, a-methylbenzylamine,
1-(2-naphthyl)ethylamine, quinidine, quinine, strychnine, valine
and all other chiral bases that can lead to resolution of racemic
mixture. For example, a chiral salt of the compound can be
represented by:
##STR00016##
[0084] In certain embodiments, the present disclosure provides a
process for preparing a compound of Formula (I):
##STR00017##
[0085] the process comprising, providing a mixture of a compound of
Formula (II):
##STR00018##
[0086] and a compound of Formula (III):
##STR00019##
[0087] and contacting the mixture with a base (e.g., in a solvent
such as tetrahydrofuran); thereby forming a compound of Formula
(I).
[0088] Contacting may be performed at a temperature less than or
equal to 10.degree. C., e.g., may comprise stirring for about 5
minutes and/or is performed at a reaction temperature which is
maintained between -10 to 10.degree. C., for example, between -5 to
0.degree. C. The base may be an alkali metal alkoxide, e.g.,
selected from the group consisting of sodium methoxide, lithium
methoxide, and potassium methoxide, for example, sodium
methoxide.
[0089] In some embodiments, provided herein is a compound
represented by:
##STR00020##
[0090] or a pharmaceutically acceptable salt or stereoisomer
thereof.
[0091] In some embodiments, a compound of Formula (I) may exist as
a mixture of stereoisomers. Contemplated stereoisomers of Formula
(I) include e.g., compounds of Formula (a), Formula (b), Formula
(c), or Formula (d):
##STR00021##
[0092] Also provided herein in part is a process for preparing a
substantially optically pure compound of Formula (VI):
##STR00022##
[0093] the process comprising: reacting a compound of Formula
(I):
##STR00023##
[0094] with an activating agent, in the optional presence of a
base, to form an intermediate of Formula (I-A):
##STR00024##
[0095] wherein LG is a leaving group;
[0096] treating the intermediate of Formula (I-A) with a base
solution in the presence of an alcohol solvent, to eliminate the
leaving group and thereby forming an intermediate of Formula
(I-B):
##STR00025##
[0097] hydrolyzing the intermediate of Formula (I-B) to form a
compound of Formula (IV):
##STR00026##
[0098] hydrogenating the compound of Formula (IV) to form a
compound of Formula (V):
##STR00027## [0099] resolving the compound of Formula (V) to form a
substantially optically pure compound of Formula (VI), wherein the
process and variables are as defined herein.
[0100] Procedures for making compounds described herein are
provided below with reference to Schemes 1-21. In the reactions
described below, it may be necessary to protect reactive functional
groups (such as hydroxyl, amino, or carboxyl groups) to avoid their
unwanted participation in the reactions. The incorporation of such
groups, and the methods required to introduce and remove them are
known to those skilled in the art (for example, see Greene, Wuts,
Protective Groups in Organic Synthesis. 4th Ed. (2007)). The
deprotection step may be the final step in the synthesis such that
the removal of protecting groups affords compounds of Formula I, as
disclosed herein. Starting materials used in the following schemes
can be purchased or prepared by methods described in the chemical
literature, or by adaptations thereof, using methods known by those
skilled in the art. The order in which the steps are performed can
vary depending on the groups introduced and the reagents used, but
would be apparent to those skilled in the art.
EXAMPLES
[0101] The procedures disclosed herein can be conducted in a number
of ways based on the teachings contained herein and synthetic
procedures known in the art. In the description of the synthetic
methods described below, it is to be understood that all proposed
reaction conditions, including choice of solvent, reaction
atmosphere, reaction temperature, duration of the experiment and
workup procedures, can be chosen to be the conditions standard for
that reaction, unless otherwise indicated. It is understood by one
skilled in the art of organic synthesis that the functionality
present on various portions of the molecule should be compatible
with the reagents and reactions proposed. Substituents not
compatible with the reaction conditions will be apparent to one
skilled in the art, and alternate methods are therefore indicated.
The starting materials for the examples are either commercially
available or are readily prepared by standard methods from known
materials.
[0102] At least some of the compounds identified as intermediates
e.g., as part of a synthetic scheme disclosed herein are
contemplated as compounds of the disclosure
Abbreviations:
General:
[0103] APCI atmospheric pressure chemical ionization DSC
differential scanning calorimetry EA elemental analysis ESI
electrospray ionization GC gas chromatography HPLC high-performance
liquid chromatography ICP-AES inductively coupled plasma atomic
emission spectroscopy LC liquid chromatography MHz megahertz MS
mass spectrometry NMR nuclear magnetic resonance TLC thin layer
chromatography Me methyl Ph phenyl Et ethyl
Solvents and Reagents
[0104] CSA camphorsulfonic acid
DMF N,N-dimethylformamide
[0105] EtOAc ethyl acetate Mesyl methanesulfonyl NaOMe sodium
methoxide THF tetrahydrofuran
General Experimental:
[0106] .sup.1NMR spectra were recorded using a Varian Gemini 200
NMR-spectrometer operating at 200 MHz or 600 MHz. Chemical shifts
for protons were reported as parts per million in 6 scale using
solvent residual peak (DMSO-d.sub.6: 2.50 ppm) as an internal
standard. Data are represented as follows: chemical shift
(.delta.), multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, qn=quintuplet, sx=sextet, sp=septuplet, m=multiplet,
br=broad, dd=doublet of doublets, dt=doublet of triplets,
qd=quartet of doublets, dquin=doublet of quintets), coupling
constant (J, Hz) and integration (# H).
[0107] .sup.13C NMR were recorded dissolving the sample in
DMSO-d.sub.6 operating at 600 MHz. Full decoupled spectra were
acquired.
[0108] Mass spectra were recorded on an Thermo-Finnigan
LCQ-Advantage mass-spectrometer or MS Thermo LCQ-fleet. The LC/MS
data were obtained using positive/negative mode switching or using
a negative mode polarity with acquisition parameters optimized in
negative polarity on signal 236 m/z corresponding to the
quasi-molecular ion [M-H].sup.- of the sample.
[0109] The elemental analysis (CHN) was carried out by Carlo Erba
EA1108 equipment under the following conditions: sample weight:
0.5-2 mg; furnace temperature: 1010.degree. C.; column temperature:
80.degree. C.; gas: He; flow: 100 mL/min. The elemental analysis
(Oxygen) was carried out by Carlo Erba EA1108 equipment under the
following conditions: sample weight: 0.5-2 mg; furnace temperature:
1010.degree. C.; column temperature: 60.degree. C.; gas: He; flow:
100 mL/min.
[0110] FT-IR spectroscopy FT-IR/ATR was performed on the sample as
such with a Perkin Elmer spectrometer model Spectrum Two instrument
equipped with a diamond probe. The spectrum was collected in the
frequency range of 450-4000 cm.sup.-1.
[0111] UV-visible spectrum was recorded with a spectrophotometer
Shimadzu UV 2600 working under the following conditions: cuvette:
quartz 1 cm; range: 200-600 nm; scan speed: medium; scan step: 1
nm; slit width: 1.0 nm; Reference solution: methanol; sample
solution: 1 mg of sample was dissolved in 100 mL of methanol.
[0112] DSC was performed using a Mettler-Toledo TGA-DSC1 instrument
working in the following conditions (pan: aluminum (open); heating
rate: 10.degree. C./min; gas: Nitrogen; flow: 30 mL/min).
[0113] Specific optical rotation was determined as follows. In a 50
mL volumetric flask accurately weigh 0.5 g of the sample, dissolve
and dilute to volume with methanol (concentration: 10 mg/mL
corresponding to 1% w/v). Determine the rotation angle of the
obtained solution, using a polarimeter tube having an optical
length corresponding to 1 dm.
[0114] Calculate the specific optical rotation
[.alpha.].sub.D.sup.20 referred to the dried substance with the
following formula: (.alpha..times.50.times.100)/(W.times.(100-m)),
where .alpha.=read rotation angle; W=sample weight (g); and
m=sample water content (%).
[0115] Chiral purity (HPLC) was determined as follows.
TABLE-US-00001 Apparatus and operative conditions Chromatograph
HPLC Waters equipped with pump, injector, UV-Vis spectrophotometer
and Empower integration system (or equivalent) Column
DaicelChiralpak WH, 10 .mu.m 250 mm .times. 4.6 mm I.D. (Daicel
Chemical Industries DAIC25625) Mobile phase A dissolve 62.5 mg of
CuSO.sub.4.cndot.5H.sub.2O in 1000 mL of water Mobile phase Prepare
a 90:10 (v/v) mixture of Mobile phase A/ acetonitrile Flow rate 1.0
mL/min Column 45.degree. C. temperature Injected 20 .mu.l volume
Wavelength 258 nm
Preparation of the Solutions
[0116] Sample solution: in a 10 mL volumetric flask accurately
weigh 10 mg of the sample, then dissolve and dilute to volume with
mobile phase (concentration: 1000 .mu.g/mL). [0117] Reference
solution : in a 100 mL volumetric flask accurately weight 10 mg of
(R,S)-3-(4-Acetamidophenyl)-2-methoxypropionic acid standard, then
dissolve and dilute to volume with mobile phase. [0118] System
suitability test (SST) solution: in a 10 mL volumetric flask
accurately weight 10 mg of
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid standard, add
2 mL of reference solution, then dissolve and dilute to volume with
mobile phase (final concentration of the dextrorotatory enantiomer:
10 .mu.g/mL corresponding to 1% with reference to the sample
solution, corresponding to 99% of chiral purity of
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid).
System Suitability Test and Procedure
[0119] Inject 20 .mu.l of the sample solution and of SST solution
in the chromatograph and record the chromatogram.
[0120] The elution order of the main peaks is as follows.
(R)-(+)-3-(4-Acetamidophenyl)-2-methoxypropionic acid
(dextrorotatory enantiomer): RRT=0.9; and
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid (levorotatory
enantiomer): RRT=1.0.
[0121] The chromatographic system can be used for the test if the
h/v ratio is not less than 1.5, where h is the distance between the
top of the peak due to the dextrorotatory enantiomer and the
baseline, v is the distance between the lowest point of the valley
defined between dextrorotatory enantiomer peak and levorotatory
enantiomer one and the baseline.
[0122] The chiral purity % is calculated from the following
expression: (A.sub.1.times.100)/(A.sub.1+A.sub.d), where
A.sub.1=(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid peak
area in the sample solution (levorotatory enantiomer) and
A.sub.d=(R)-(+)-3-(4-Acetamidophenyl)-2-methoxypropionic acid peak
area in the sample solution (dextrorotatory enantiomer).
[0123] The above method may be used to determine optical purity or
enantiomeric purity of a compound as referenced herein.
Example 1: Preparation of methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I)
##STR00028##
TABLE-US-00002 [0124] TABLE 1 Batch formula at production scale
(synthesis of compound (I)) Material Factor* Amount (kg) sodium
methoxide 0.6 30.0 THF 1.5 75 4-nitrobenzaldehyde 1.0 50 methyl
methoxyacetate 1.1 55 THF 2.0 100 THF 0.5 25.0 cold toluene 2.0 100
glacial acetic acid 1.0 50 deionized water 3.0 150 deionized water
2.0 100 sodium chloride 0.2 10 deionized water 2.0 100 sodium
chloride 0.2 10 toluene 1.0 50 toluene 1.5 75 cold toluene 0.5 25
*factor is referenced to the amount of 4-nitrobenzaldehyde used
Preparation of 4-Nitrobenzaldehyde in Methyl Methoxyacetate and
Tetrahydrofuran Suspension:
[0125] A stainless steel reactor was charged with
4-nitrobenzaldehyde (50 kg), methyl methoxyacetate (55 kg) and
tetrahydrofuran (100 kg) and cooled to -5 to +5.degree. C. while
stirring.
Preparation of methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):
[0126] A stainless steel reactor was flushed with nitrogen
(2.times.), and charged with sodium methoxide (30.0 kg) and
tetrahydrofuran (75 kg) while flushing with nitrogen. The reactor
was then flushed with nitrogen for 1 min and the sodium methoxide
solution cooled to -10 to -5.degree. C., while stirring. The cooled
solution was then treated with the previously prepared suspension
of 4-nitrobenzaldehyde in methyl methoxyacetate and tetrahydrofuran
maintaining the temperature of the reaction mass below 10.degree.
C. After the addition was complete, the empty reactor was rinsed
with tetrahydrofuran (25.0 kg) and poured into the reaction. The
reaction was stirred at -10 to +10.degree. C. for no more than 5
minutes. Maintaining the temperature at -10 to +10.degree. C., cold
toluene (100 kg, -10 to 0.degree. C.) followed by glacial acetic
acid (50 kg) were slowly added and the reaction stirred for 10
minutes at -10 to +10.degree. C. Deionized water (150 kg) was added
and the reaction mass stirred at 0 to 10.degree. C. for at least 10
minutes, then at 20 to 30.degree. C. for at least 10 minutes to
ensure complete dissolution, after which time stirring was stopped
and the phases allowed to separate. The aqueous phase was
eliminated, and the separated organic phase was treated with
aqueous sodium chloride solution (previously prepared by adding 10
kg of sodium chloride to 100 kg of deionized water). The mass was
then heated to 50 to 60.degree. C., while stirring for at least 10
minutes. Stirring was stopped and the phases allowed to separate.
The aqueous phase was eliminated and the organic phase treated with
sodium chloride (previously prepared by adding 10 kg of sodium
chloride with 100 kg of deionized water). The mass was extracted
once more using the same protocol. The separated organic phase was
then distilled under vacuum, without exceeding 80.degree. C. to
remove THF. The reactor containing the hot residue was flushed with
nitrogen then treated with toluene (50 kg), and the toluene
distilled under vacuum, without exceeding 80.degree. C. The
resulting hot residue was flushed with nitrogen then treated with
toluene (75 kg) and the mass stirred for at least 30 minutes at 30
to 45.degree. C. to ensure good product precipitation. The mixture
was then cooled to -10 to 0.degree. C. and stirred at for at least
1 hour at that temperature. The resulting suspension was
centrifuged portion-wise, washing with cold toluene (25 kg) to
obtain wet methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate
(I) (84 kg), which was used directly.
[0127] Methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I):
IR: 3468, 1737, 1514, 1350, 1201, 1101 cm.sup.-; LCMS (-)APCI: m/z
calculated for C.sub.11H.sub.13NO.sub.6: 255, found: 254 (M-H);
.sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 8.16 (AA'BB' system,
J=8.8 Hz, 2 H), 7.62 (AA'BB' system, J=8.8 Hz, 2 H), 5.97 (d, J=6.0
Hz, 1 H), 5.05 (dd, J=6.0, 4.0 Hz, 1 H), 4.10 (d, J=4.0 Hz, 1 H),
3.60 (s, 3 H), 3.20 (s, 3 H); .sup.13C NMR (150 MHz, DMSO-d6):
.delta. 170.2, 149.4, 146.7, 127.8, 122.9, 84.1, 72.7, 58.2, 51.6;
UV-Vis (MeOH): .lamda..sub.max 202, 270; Anal. calcd for:
(C.sub.11H.sub.13NO.sub.6): C 51.97; H 5.16; N 5.42; O 37.52.
Example 2: Preparation of
(S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid (VI) and
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid (VII)
##STR00029## ##STR00030##
[0128] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic Acid
(IV):
##STR00031##
TABLE-US-00003 TABLE 2 Batch formula at production scale (synthesis
of compound (IV)) Material Factor* Amount (kg) methyl
3-hydroxy-2-methoxy-3- 1.0 84 (72.6 (4-nitrophenyl)propanoate, wet
kg as dried) toluene 3.9 283 triethylamine 0.5833 42.3
methanesulfonyl chloride 0.5 36.3 deionized water 2.0 145 toluene
0.1 7.3 methanol 3.0 218 sodium hydroxide 30% 1.3 94 deionized
water 4.0 290 phosphoric acid 85% 1.3 94 phosphoric acid 85% -- to
pH .ltoreq.3.0 deionized water 0.5 36.3 toluene 1.0 73 deionized
water 2.0 145 *factor is referenced to the amount of methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (as dried) used
[0129] A stainless steel reactor flushed with nitrogen (2.times.)
was loaded with wet methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate (I) (84 kg) and
toluene (283 kg) then cooled to 0 to 10.degree. C. while flushing
with nitrogen. Maintaining the temperature at 0 to 10.degree. C.
triethylamine (42.3 kg) and methanesulfonyl chloride (36.3 kg) were
added, and the reaction stirred at 0 to 10.degree. C. for 30
minutes. Deionized water (145 kg) was slowly added, and the
resulting mass stirred at 50 to 60.degree. C. for 10 minutes, after
which time stirring was stopped and the phases were allowed to
separate. The aqueous phase was eliminated and the organic phase
filtered washing with toluene (7.3 kg). The toluene was removed by
distillation under vacuum and without exceeding 60.degree. C., to
obtain an oily residue. The resulting residue was then treated with
methanol (218 kg), transferred to another reactor, flushed with
nitrogen, cooled to 20 to 30.degree. C. and treated slowly with 30%
sodium hydroxide (94 kg). The reaction was stirred at 20 to
30.degree. C. for 2 hours. Deionized water (290 kg) was added, and
the solution heated to 55 to 65.degree. C. At this temperature, 85%
phosphoric acid (94 Kg) was slowly added until a pH <3.0 was
obtained. The resulting precipitated product was stirred at 55 to
65.degree. C. for at least 30 minutes then cooled to 25 to
30.degree. C., and stirred for at least 30 minutes. The mixture was
centrifuged washing with deionized water (36.3 kg), toluene (73
kg), and deionized water (145 kg). The product was granulated and
dried at 70 to 80.degree. C. to deliver
2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg).
[0130] Methyl
2-methoxy-3-((methylsulfonyl)oxy)-3-(4-nitrophenyl)propanoate
(I-A1) LCMS (+)ESI: m/z calculated for C.sub.12H.sub.15NO.sub.8S:
333; found 356 (M+Na); .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.
8.25 (AA'BB' system, J=8.5 Hz, 2 H), 7.72 (AA'BB' system, J=8.5 Hz,
2 H), 6.00 (d, J=4.0 Hz, 1 H), 4.41 (d, J=4.0 Hz, 1 H), 3.65 (s, 3
H), 3.21 (s, 3 H), 3.11 (s, 3 H).
[0131] Methyl 2-methoxy-3-(4-nitrophenyl)acrylate (I-B): LCMS
(-)APCI: m/z calculated for C.sub.11H.sub.11NO.sub.5: 237; found
236 M-H); .sup.1H NMR (200 MHz, DMSO-d.sub.6): .differential. 8.20
(AA'BB' system, J=8.8 Hz, 2 H), 7.99 (AA'BB' system, J=8.8 Hz, 2
H), 6.98 (s, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H).
[0132] 2-Methoxy-3-(4-nitrophenyl)acrylic acid (IV): LCMS (-)APCI:
m/z calculated for C.sub.10H.sub.9NO.sub.5: 223, found: 222 (M-H);
.sup.1H NMR (200 MHz, DMSO-d6): .delta. 13.37 (s, 1 H), 8.21
(AA'BB' system, J=9.1 Hz, 2 H), 7.98 (AA'BB' system, J=9.1 Hz, 2
H), 6.93 (s, 1 H), 3.79 (s, 3 H).
Preparation of 3-(4-aminophenyl)-2-methoxypropanoic Acid (V):
##STR00032##
TABLE-US-00004 TABLE 3 Batch formula at production scale (synthesis
of compound (V)) Material Factor* Amount (kg) 2-methoxy-3-(4- 1.0
50.4 nitrophenyl)acrylic acid, dried methanol 5.0 252
N,N-dimethylformamide 0.3421 17.2 palladium on carbon 5% 0.1 7.7
(containing 50% water) N,N-dimethylformamide 0.0526 2.65
N,N-dimethylformamide 0.0526 2.65 N,N-dimethylformamide 0.0526 2.65
ammonia (30%) 0.4 20.2 deionized water 0.25 12.6 deionized water
0.5 25.2 deionized water 3.0 151 acetic acid 80% 0.5 25.2 ethyl
acetate 1.0 50 deionized water 2.0 101 ethyl acetate 0.5 25.2
*factor is referenced to the amount of dried
2-methoxy-3-(4-nitrophenyl)acrylic acid used
[0133] A suitable stainless steel reactor was loaded with
N,N-dimethylformamide (17.2 kg), 5% palladium on carbon (7.7 kg)
and N,N-dimethylformamide (2.times.2.65 kg) and the suspension
stirred thoroughly.
[0134] A stainless steel reactor flushed with nitrogen (2.times.)
charged with methanol (252 kg) was cooled to 0 to 10.degree. C. and
dry 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV) (50.4 kg) was
added. The resulting solution was flushed with nitrogen (2.times.)
and treated with a previously prepared solution of 5% palladium on
carbon in N,N-dimethylformamide, and the empty vessel was washed
with N,N-dimethylformamide (2.65 kg). The reaction was flushed with
nitrogen (2.times.), heated to 60 to 80.degree. C. then charged
with hydrogen until a pressure of 3.5 and 4.5 atm was obtained. The
reaction was allowed to proceed, maintaining the pressure between
3.5 and 4.5 atm until hydrogen consumption ceased and the reaction
was confirmed complete. The reactor was restored to atmospheric
pressure and the reaction was cooled to 20 to 30.degree. C.,
flushed with nitrogen (2.times.) and treated sequentially with 30%
ammonia (20.2 kg) and deionized water (12.6 kg), stirring at 20 to
30.degree. C. until complete dissolution occurred. The solution was
filtered through sparkler filter washing with deionized water (25.2
kg). The reactor was flushed with nitrogen, and the solvents were
removed by vacuum distillation, at a temperature not exceeding
70.degree. C. The residue was treated with deionized water (151
kg), heated to 60 to 70.degree. C. and the product precipitated by
adding 80% acetic acid (25.2 kg). The mixture was stirred at 60 to
70.degree. C. for at least 10 minutes then treated with ethyl
acetate (50 kg), flushed with nitrogen and stirred at 60 to
70.degree. C. for at least 15 minutes. The reaction mass was cooled
to 10 to 20.degree. C. and stirred for at least 30 minutes. The
suspension was centrifuged portion-wise washing with deionized
water (101 kg) and ethyl acetate (25.2 kg). The moist product was
granulated, and dried at 60 to 70.degree. C. to obtain
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (-37.5 kg).
[0135] 3-(4-Aminophenyl)-2-methoxyacrylic acid (I-C): LCMS (+)ESI:
m/z calculated for C.sub.10H.sub.11NO.sub.3: 193, found 194 (M+H);
.sup.1H NMR (200 MHz, DMSO-d6): .delta. 12.00 (br s, 1 H), 7.43
(AA'BB' system, J=8.4 Hz, 2 H), 6.76 (s, 1 H), 6.53 (AA'BB' system
, J=8.4 Hz, 2 H), 5.80 (br s, 2 H), 3.61 (s, 3 H).
[0136] 3-(4-Aminophenyl)-2-methoxypropanoic acid (V): IR: 3044,
2950-2830, 2623-2064, 1618-1516, 1106 cm.sup.-1; LCMS (+)ESI: m/z
calculated for C.sub.10H.sub.13NO.sub.3: 195, found 196 (M+H);
.sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta. 8.40-6.40 (br s, 3 H),
6.83 (AA'BB' system, J=8.1 Hz, 2 H), 6.41 (AA'BB' system, J=8.1 Hz,
2 H), 3.77 (ABX system, J=7.5, 5.3 Hz, 1 H), 3.19 (s, 3 H), 2.74
(ABX system, J=13.9, 5.3 Hz, 1 H), 2.65 (ABX system, J=13.9, 7.5
Hz, 1 H). Anal. calcd for: (C.sub.10H.sub.13NO.sub.3): C 61.40; H
6.81; N 7.11; O 24.91.
Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic Acid Salt:
##STR00033##
TABLE-US-00005 TABLE 4 Batch formula at production scale (synthesis
of compound (VI).cndot.(S)-CSA) Material Factor* Amount (kg)
3-(4-aminophenyl)-2- 1.0 37.5 methoxypropanoic acid acetone 3.0 113
deionized water 0.4 15.0 (S)-(+)-10-camphor-sulfonic acid 1.2321
46.2 acetone 2.0 75 (S)-(-)-3-(4-Aminophenyl)-2- 0.01 0.38
methoxypropionic acid S-(+)- camphor-10-sulfonic acid salt, dried
(primer) acetone 2.0 75 *factor is referenced to the amount of
3-(4-aminophenyl)-2-methoxypropanoic acid (dried) used
[0137] A stainless steel reactor was loaded with
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (37.5 kg), and
acetone (113 kg) while flushing with nitrogen. Deionized water
(15.0 kg) and (S)-(+)-camphor-10-sulfonic acid (46.2 kg) were added
and the reactor flushed with nitrogen. The reaction was heated to
45 to 55.degree. C. until dissolution was complete. Acetone (75 kg)
was added and the solution cooled to 30 to 35.degree. C. and
treated with primer (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic
acid S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (0.38 kg).
The reaction was stirred at 30 to 35.degree. C. for at least 3
hours until good precipitation occurred. The suspension was
centrifuged portion-wise washing with acetone (75 kg). The
centrifuged product (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic
acid S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (41.7 kg) was
used directly in the next step.
[0138] Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic
Acid (VI):
##STR00034##
TABLE-US-00006 TABLE 5 Batch formula at production scale (synthesis
of compound (VI)) Material Factor* Amount (kg)
(S)-(-)-3-(4-Aminophenyl)-2- 1.0 41.7 (35.0 methoxypropionic acid
S-(+)- kg as dried) camphor-10-sulfonic acid salt, wet deionized
water 2.8 98 deionized water 0.2 7.0 ethyl acetate 1.0 35.0 ammonia
30% 0.1792 6.3 acetic acid 80% 0.125 4.38 deionized water 0.5 17.5
ethyl acetate 0.5 17.5 deionized water 0.5 17.5 *factor is
referenced to the amount of
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt used (as dried).
Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic Acid
(VI):
[0139] A stainless steel reactor was charged with deionized water
(98 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (41.7 kg), flushed
with nitrogen and heated for at least 10 minutes at 20 to
30.degree. C. until complete dissolution occurs. The solution was
filtered washing with deionized water (7.0 kg), then ethyl acetate
(35.0 kg). The resulting solution was flushed with nitrogen, heated
to 50 to 60.degree. C. and 30% ammonia (6.3 kg) was added to
precipitate the product. The resulting mixture was stirred for at
least 5 minutes at 50-60.degree. C. then 80% acetic acid (4.38 kg)
was added through a filter and the reaction flushed with nitrogen
and stirred at 50 to 60.degree. C. for at least 30 minutes then
cooled down to 10-20.degree. C. and stirred for at least 1 hour.
The reaction was centrifuged portion-wise and washed with deionized
water (17.5 kg), ethyl acetate (17.5 kg) and deionized water (17.5
kg), and dried at 50-60.degree. C. to deliver
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (9.6 kg,
27%), which was used directly in the next step.
[0140] (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid (VI):
[.alpha.].sub.D.sup.20 -30 to -26 (1% w/v H.sub.2O/CH.sub.3OH (1:1
v/v)); IR: 2931, 2891, 2826, 2625, 2136, 1587, 1548, 1512, 1106,
1092 cm.sup.-1; LCMS (+) ESI: m/z calculated for
C.sub.10H.sub.13NO.sub.3: 195, found 196 (M+H); .sup.1H NMR (200
MHz, DMSO-d.sub.6): .delta. 9.0-6.0 (br s, 3 H), 6.83 (AA'BB'
system, J=8.1 Hz, 2 H), 6.43 (AA'BB' system, J=8.1 Hz, 2 H), 3.76
(ABX system , J=7.5, 5.3 Hz, 1 H), 3.19 (s, 3 H), 2.75 (ABX system
, J=13.9, 5.3 Hz, 1 H), 2.65 (ABX system , J=13.9, 7.5 Hz, 1 H).
Anal. calcd for: (C.sub.10H.sub.13NO.sub.3): C, 61.45; H, 6.79; N
7.12; O 24.65.
Preparation of (S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic
acid (VII):
##STR00035##
TABLE-US-00007 TABLE 6 Batch formula at production scale (synthesis
of compound (VII)) Material Factor* Amount (kg)
(S)-(-)-3-(4-Aminophenyl)-2- 1.0 9.6 methoxypropionic acid ethyl
acetate 1.5 14.4 acetic anhydride 0.5833 5.6 deionized water 0.05
0.5 ethyl acetate 0.5 4.80 deionized water 1.5 14.4 *factor is
referenced to the amount of
(S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid used
[0141] A stainless steel reactor was charged with dry
(S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (9.6 kg) and
ethyl acetate (14.4 kg) at 0 to 10.degree. C., while flushing with
nitrogen. The reaction mass was heated to 60 to 70.degree. C. and
acetic anhydride (5.6 kg) was added through a cartridge filter over
about 30 minutes. The reaction was stirred at 60 to 70.degree. C.
for 1 hour, then treated with deionized water (0.5 kg) and stirred
at 60 to 70.degree. C. for at least 15 minutes during which time a
precipitate formed. The mixture was cooled to 10 to 20.degree. C.
and stirred for at least 30 minutes, then centrifuged and the
resulting solid washed with ethyl acetate (4.80 kg), and deionized
water (14.4 kg). The resulting product was dried at 60 to
70.degree. C. for 13-16 hours, and milled to obtain
(S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (10.3
kg).
[0142] (S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid:
(VII): [.alpha.].sub.D.sup.20 -26 to -19 (1% w/v
H.sub.2O/CH.sub.3OH (1:1 v/v)); IR: 3322, 3089, 2930, 2827, 2714,
2490, 1722, 1637, 1601, 1551, 1516, 1231, 1207, 1120, 1110
cm.sup.-1; LCMS (+)ESI: m/z calculated for
C.sub.12H.sub.15NO.sub.4: 237, found 238 (M+H); .sup.1H NMR (200
MHz, DMSO-d.sub.6): .delta. 12.96 (s, 1 H), 9.84 (s, 1 H), 7.43
(AA'BB' system, J=8.5 Hz, 2 H), 7.10 (AA'BB' system , J=8.5 Hz, 2
H), 3.86 (ABX system, J=7.6, 5.2 Hz, 1 H), 3.00 (s, 3 H), 2.95-2.70
(ABX system, J=13.9, 7.6, 5.2 Hz, 2 H), 2.00 (s, 3 H).
TABLE-US-00008 TABLE 7 (S)-3-(4-acetamidophenyl)-2-methoxypropanoic
acid (VII) specifications as prepared by Scheme 7
(S)-(+)-camphor-10-sulfonic acid No more than 0.1% (HPLC)
(S)-3-(4-aminophenyl)-2- No more than 0.15% (HPLC) methoxypropanoic
acid Other impurity No more than 0.1% (HPLC) Palladium No more than
10 ppm (ICP-AES) Chiral purity Not less than 98% (HPLC) Acetic acid
No more than 5000 ppm (GC) Residual solvents (ethyl acetate) No
more than 5000 ppm (GC)
Example 3: Preparation of methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):
##STR00036##
TABLE-US-00009 [0143] TABLE 8 Batch formula at production scale
(synthesis of compound (I)) Material Factor* Amount (kg) sodium
methoxide 0.6 28.5 THF 2.5 119 4-nitrobenzaldehyde 1.0 47.5 methyl
1.1 52 THF 1.0 47.5 THF 0.5 23.8 cold toluene 2.0 95 glacial acetic
acid 0.75 36 deionized water 3.0 143 deionized water 1.0 48 sodium
chloride 0.1 4.75 toluene 1.0 47.5 toluene 4.65 221 *factor is
referenced to the amount of 4-nitrobenzaldehyde used
Preparation of 4-nitrobenzaldehyde in Methyl Methoxyacetate and
Tetrahydrofuran Suspension:
[0144] A stainless steel reactor was charged with
4-nitrobenzaldehyde (47.5 kg), methyl methoxyacetate (52 kg) and
tetrahydrofuran (47.5 kg) and cooled to -10 to -5.degree. C. while
stirring. Preparation of methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):
[0145] A stainless steel reactor was flushed with nitrogen
(2.times.), and charged with sodium methoxide (28.5 kg) and
tetrahydrofuran (119 kg) while flushing with nitrogen. The reactor
was then flushed with nitrogen for 1 min and the sodium methoxide
solution was cooled to -10 to -7.degree. C., while stirring. The
cooled solution was then treated with the previously prepared
suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and
tetrahydrofuran while maintaining the temperature of the reaction
mass below 0.degree. C. After the addition was complete, the empty
reactor was rinsed with tetrahydrofuran (23.8 kg) and poured into
the reaction. The reaction was stirred at -5 to 0.degree. C. for no
more than 5 minutes. Maintaining the temperature at -10 to
0.degree. C., cold toluene (95 kg, -10 to 0.degree. C.) was quickly
added and then, after, glacial acetic acid (36 kg) was quickly
added and the reaction was stirred for 10 minutes at -10 to
+10.degree. C. Deionized water (143 kg) was added and the reaction
mass was stirred at 0 to 10.degree. C. for at least 10 minutes,
then at 25 to 30.degree. C. for at least 10 minutes to ensure
complete dissolution, after which time stirring was stopped and the
phases were allowed to separate. The aqueous phase was eliminated,
and the separated organic phase was treated with aqueous sodium
chloride solution (previously prepared by adding 4.75 kg of sodium
chloride to 48 kg of deionized water). The mass was then heated to
25 to 30.degree. C., while stirring for at least 15 minutes.
Stirring was stopped and the phases were allowed to separate. The
aqueous phase was eliminated (64 kg). The separated organic phase
was then distilled up to oily residue under vacuum, up to a
temperature of 70 to 80.degree. C. The reactor containing the hot
residue was flushed with nitrogen then treated with toluene (47.5
kg), and the toluene was distilled under vacuum, up to a
temperature of 70 to 80.degree. C., obtaining an oily residue. The
resulting hot residue was flushed with nitrogen then treated with
toluene (221 kg) and the mass was stirred for at least 10 minutes
at 40 to 50.degree. C. The solution was employed as is in the
subsequent step.
Example 4: Process for the Preparation of
(S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic Acid (VI) and
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic Acid (VII)
##STR00037##
[0146] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic Acid
(IV):
##STR00038##
TABLE-US-00010 TABLE 9 Batch formula at production scale (synthesis
of compound (IV)) Material Factor* Amount (kg) methyl
3-hydroxy-2-methoxy-3- 1.0 All solution obtained
(4-nitrophenyl)propanoate, in Scheme 8 solution in toluene
triethylamine 0.9 42.8 methanesulfonyl chloride 0.8 38 deionized
water 3.0 143 Toluene 0.15 7.1 methanol 3.1 147 sodium hydroxide
30% 1.86 88 deionized water 3.88 184 hydrochloric acid 37% 0.74
35.2 phosphoric acid 85% 0.16 7.6 phosphoric acid 85% -- to pH
.ltoreq.3.0 deionized water 4.0 190 toluene 2.4 114 *factor is
referenced to the amount of 4-nitrobenzaldehyde used
[0147] The methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate
(I) in toluene solution in a stainless steel reactor was cooled to
0 to 10.degree. C. while flushing with nitrogen, and while
maintaining the temperature at 0 to 10.degree. C. triethylamine
(42.8 kg) and methanesulfonyl chloride (38 kg) were added, and the
reaction was stirred at 0 to 10.degree. C. for 60 minutes.
Deionized water (143 kg) was slowly added, and the resulting mass
was stirred at 55 to 60.degree. C. for 10 minutes, after which time
stirring was stopped and the phases were allowed to separate. The
aqueous phase was eliminated (199 kg) and the organic phase was
filtered washing the filter with toluene (7.1 kg). The filtered
solution was heated to 55 to 60.degree. C. for 10 minutes. Stirring
was stopped and the phases were allowed to separate; the possible
aqueous phase was sent to the waste (3.5 kg). Under vacuum and
under stirring an aliquot of the toluene was distilled taking into
consideration the following proportion: for 50 kg of
nitrobenzaldehyde used in Scheme 8, approximately 5 kg of toluene
was distilled and this aliquot of distilled toluene was sent to
waste. The toluene was removed by distillation under vacuum and
without exceeding 60.degree. C., to obtain an oily residue. The
resulting residue was then treated with methanol (147 kg), flushed
with nitrogen, cooled to 20 to 30.degree. C. and treated slowly
with 30% sodium hydroxide (88 kg). The reaction was stirred at 20
to 30.degree. C. for 3 hours. Deionized water (184 kg) was added,
and the solution heated to 60 to 65.degree. C. At this temperature,
37% hydrochloric acid (35.2 kg) and 85% phosphoric acid (7.6 kg)
were slowly added to precipitate the product. If necessary, 85%
phosphoric acid was added to obtain pH.ltoreq.3.0. The resulting
precipitated product was stirred at 60 to 65.degree. C. for at
least 30 minutes then cooled to 35 to 40.degree. C., and stirred
for at least 30 minutes. The mixture was centrifuged washing with
deionized water (190 kg) and then washed with toluene (114 kg),
(mother liquor: 749 kg). The wet product (about 82 kg) was used in
the next step.
[0148] Preparation of 3-(4-aminophenyl)-2-methoxypropanoic Acid
(V):
##STR00039##
TABLE-US-00011 TABLE 10 Batch formula at production scale
(synthesis of compound (V)) Material Factor* Amount 2-methoxy-3-(4-
nitrophenyl)acrylic 1.0 82 acid, wet methanol 3.0 143 Ammonia 30%
0.3 14.3 deionized water 0.2 9.5 palladium on carbon 5% (containing
0.1 4.75 50% water) or palladium on carbon 5% (recycled) deionized
water 0.05 2.4 deionized water 0.05 2.4 deionized water 0.05 2.4
deionized water 0.4 19 deionized water 2.0 95 hydrochloric acid 37%
0.32 15.2 acetic acid 80% 0.22 10.5 ethyl acetate 1.5 71 deionized
water 1.0 47.5 ethyl acetate 1.0 47.5 *factor is referenced to the
amount of 4-nitrobenzaldehyde used
Preparation of Aqueous Suspension of Palladium at 5% on Carbon in
Water:
[0149] A suitable stainless steel reactor was loaded with deionized
water (9.5 kg), 5% palladium on carbon (4.75 kg) and then the bag
was washed twice with deionized water (2.times.2.4 kg).
Preparation of 3-(4-aminophenyl)-2-methoxypropanoic Acid (V):
[0150] A stainless steel reactor flushed with nitrogen (2.times.)
was loaded with and wet 2-methoxy-3-(4-nitrophenyl)acrylic acid
(IV) (82 kg), methanol (143 kg) and 30% ammonia (14.3 kg). After
restoring the atmospheric pressure, the mixture was stirred at 20
to 30.degree. C. up to complete dissolution. The resulting solution
was flushed with nitrogen (2.times.) and treated with a previously
prepared solution of 5% palladium on carbon in deionized water, and
the empty vessel was washed with deionized water (2.4 kg). The
reaction was flushed with nitrogen (2.times.), heated to 60 to
80.degree. C. then charged with hydrogen until a pressure of 4.0 to
4.5 atm was obtained. The reaction was allowed to proceed,
maintaining the pressure between 4.0 and 4.5 atm until hydrogen
consumption ceased and the reaction was confirmed complete. The
reactor was restored to atmospheric pressure and the reaction was
cooled to 20 to 30.degree. C., filtered through sparkler filter,
flushed with nitrogen (2.times.) and treated with deionized water
(19 kg) that was combined with the solution containing the product.
Without exceeding 50.degree. C., the solvent was distilled under
stirring and under vacuum up to oily residue. The residue was
treated with deionized water (95 kg), heated to 65 to 70.degree. C.
and the product precipitated by adding 37% hydrochloric acid (15.2
kg) and 80% acetic acid (10.5 kg). The mixture was stirred at 65 to
70.degree. C. for at least 10 minutes, and then the mixture was
treated with ethyl acetate (71 kg), flushed with nitrogen and
stirred at 65 to 70.degree. C. for at least 15 minutes. The
reaction mass was cooled to 15 to 20.degree. C. and stirred for at
least 30 minutes. The suspension was centrifuged portion-wise
washing with deionized water (47.5 kg) and ethyl acetate (47.5 kg).
The moist product was dried at 60 to 70.degree. C. to obtain
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg).
Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic Acid Salt:
##STR00040##
TABLE-US-00012 TABLE 11 Batch formula at production scale
(synthesis of compound (VI).cndot.(S)-CSA) Material Factor* Amount
(kg) 3-(4-aminophenyl)-2- 1.0 40.5 methoxypropanoic acid
(S)-(+)-10-camphor-sulfonic acid 1.2321 49.9 acetone 2.0 81
deionized water 0.16 6.5 acetone 2.0 81 acetone 1.5 61 *factor is
referenced to the amount of 3-(4-aminophenyl)-2-methoxypropanoic
acid (dried) used
[0151] A stainless steel reactor was loaded with
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (40.5 kg) and
(S)-(+)-camphor-10-sulfonic acid (49.9 kg); nitrogen was flushed
and acetone (81 kg) was added. Deionized water (6.5 kg) was added.
The reaction was heated to approximately 58.degree. C. for 2 hours
(reflux, dissolution does not occur). Acetone (81 kg) was added
(temperature approximately 58.degree. C.) and the reaction mass was
kept at reflux (approx. 58.degree. C.) for 1 hour. The reaction
mass was then cooled to 37 to 42.degree. C. and was centrifuged
portion-wise washing with acetone (61 kg). The centrifuged product
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (wet weight: 43.1
kg, 36.1 kg as dried) was used directly in the next step.
[0152] Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic
acid (VI):
##STR00041##
TABLE-US-00013 TABLE 12 Batch formula at production scale
(synthesis of compound (VI)) Material Factor* Amount (kg) deionized
water 2.0 72 (S)-(-)-3-(4-Aminophenyl)-2- 1.0 43.1 (36.1
methoxypropionic acid S-(+)- kg as dried) camphor-10-sulfonic acid
salt, wet deionized water 0.2 7.2 ethyl acetate 1.0 36.1 ammonia
30% 0.1257 4.54 acetic acid 80% 0.05 1.81 deionized water 0.7 25.3
ethyl acetate 0.7 25.3 *factor is referenced to the amount of
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-
(+)-camphor-10-sulfonic acid salt used (as dried).
[0153] A stainless steel reactor was charged with deionized water
(72 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (wet weight: 43.1
kg, 36.1 kg as dried), flushed with nitrogen and heated for at
least 10 minutes at 20 to 40.degree. C. until complete dissolution
occurred. The solution was filtered and washed with deionized water
(7.2 kg), then ethyl acetate (36.1 kg). The resulting solution was
flushed with nitrogen, heated to 55 to 60.degree. C. and 30%
ammonia (4.54 kg) was added to precipitate the product. The
resulting mixture was stirred for at least 15 minutes at 55 to
60.degree. C. then 80% acetic acid (1.81 kg) was added through a
filter and the reaction flushed with nitrogen and stirred at 55 to
60.degree. C. for at least 30 minutes then cooled down to
2-7.degree. C. and stirred for at least 1 hour. The reaction mass
was centrifuged portion-wise and washed with deionized water (25.3
kg), ethyl acetate (25.3 kg) to deliver wet
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight
11.8 kg, 10.8 kg as dried), which was used (wet) directly in the
next step.
Preparation of (S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic
Acid (VII):
##STR00042##
TABLE-US-00014 TABLE 13 Batch formula at production scale
(synthesis of compound (VII)) Material Factor* Amount (kg) Wet
(S)-(-)-3-( 4-Aminophenyl)- 1.0 11.8 (10.8 2- methoxypropionic acid
kg as dried) ethyl acetate 1.5 16.2 acetic anhydride 0.65 7.0 ethyl
acetate 0.5 5.4 deionized water 1.5 16.2 *factor is referenced to
the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
used (as dried)
[0154] A stainless steel reactor was charged with wet
(S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 11.8
kg, 10.8 kg as dried) and ethyl acetate (16.2 kg), under nitrogen.
The mixture was heated to 65 to 70.degree. C. and acetic anhydride
(7.0 kg) was added through a cartridge filter over about 15
minutes. The reaction was stirred at 65 to 70.degree. C. for 60
minutes and, once the reaction end was detected, continuously
stirred until formation of a precipitate. The mixture was cooled to
10 to 20.degree. C. and stirred at 10 to 20.degree. C. for 30
minutes, then centrifuged and the resulting solid washed with ethyl
acetate (5.4 kg), and deionized water (16.2 kg). The resulting
product was dried at 60 to 70.degree. C. for 13-16 hours, and
milled to obtain (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid
(VII) (12.3 kg).
Example 5: Preparation of Methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):
##STR00043##
TABLE-US-00015 [0155] TABLE 14 Batch formula at production scale
(synthesis of compound (I)) Material Factor* Amount (kg) sodium
methoxide 0.6 228 THF 2.895 1100 4-nitrobenzaldehyde 1.0 380 methyl
1.1 418 THF 1.0 380 THF 0.105 40 cold toluene 2.0 760 glacial
acetic acid 0.75 285 deionized water 3.0 1140 deionized water 1.0
380 sodium chloride 0.1 38 toluene 1.0 380 toluene 4.65 1767
*factor is referenced to the amount of 4-nitrobenzaldehyde used
Preparation of 4-nitrobenzaldehyde in Methyl Methoxyacetate and
Tetrahydrofuran Suspension:
[0156] A stainless steel reactor was charged with
4-nitrobenzaldehyde (380 kg), methyl methoxyacetate (418 kg) and
tetrahydrofuran (380 kg) and cooled to -10 to -5.degree. C. while
stirring.
Preparation of Methyl
3-hydroxy-2-methoxy-3-(4-nitrophenyl)propionate (I):
[0157] A stainless steel reactor was flushed with nitrogen
(2.times.), and charged with sodium methoxide (228 kg) and
tetrahydrofuran (1100 kg) while flushing with nitrogen. The reactor
was then flushed with nitrogen for 1 min and the sodium methoxide
solution cooled to -15 to -10.degree. C., while stirring. The
cooled solution was then treated with the previously prepared
suspension of 4-nitrobenzaldehyde in methyl methoxyacetate and
tetrahydrofuran while maintaining the temperature of the reaction
mass below 0.degree. C. After the addition was complete, the empty
reactor was rinsed with tetrahydrofuran (40 kg) and poured into the
reaction. The reaction was stirred at -5 to 0.degree. C. for no
more than 5 minutes. Maintaining the temperature at -10 to
0.degree. C., cold toluene (760 kg, -10 to 0.degree. C.) and, at
the same time, glacial acetic acid (285 kg) were quickly added and
the reaction stirred for 10 minutes at -10 to +10.degree. C.
Deionized water (1140 kg) was added and the reaction mass stirred
at 0 to 10.degree. C. for at least 10 minutes, then at 25 to
30.degree. C. for at least 10 minutes to ensure complete
dissolution, after which time stirring was stopped and the phases
were allowed to separate. The aqueous phase was eliminated, and the
separated organic phase was treated with aqueous sodium chloride
solution (previously prepared by adding 38 kg of sodium chloride to
380 kg of deionized water). The mass was then heated to 25 to
30.degree. C., while stirring for at least 10 minutes. Stirring was
stopped and the phases allowed to separate. The aqueous phase was
eliminated. The separated organic phase was then distilled up to
oily residue under vacuum, up to a temperature of 70 to 80.degree.
C. The reactor containing the hot residue was flushed with nitrogen
then treated with toluene (380 kg), and the toluene distilled under
vacuum, up to a temperature of 70 to 80.degree. C., obtaining an
oily residue. The resulting hot residue was flushed with nitrogen
then treated with toluene (1767 kg) and the mass stirred for at
least 10 minutes at 40 to 50.degree. C. The solution was employed
as is in the subsequent step.
Example 6: Process for the Preparation of
(S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic Acid (VI) and
(S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic Acid (VII)
##STR00044##
[0158] Preparation of 2-methoxy-3-(4-nitrophenyl)acrylic Acid
(IV):
##STR00045##
TABLE-US-00016 TABLE 15 Batch formula at production scale
(synthesis of compound (IV)) Material Factor* Amount (kg) methyl
3-hydroxy-2-methoxy-3- 1.0 All solution obtained
(4-nitrophenyl)propanoate, in Scheme 15 solution in toluene
triethylamine 0.9 342 methanesulfonyl chloride 0.8 304 deionized
water 3.0 1140 Toluene 0.15 57 methanol 3.1 1178 sodium hydroxide
30% 1.86 707 deionized water 3.88 1474 hydrochloric acid 37% 0.74
281 phosphoric acid 85% 0.16 61 phosphoric acid 85% -- to pH
.ltoreq.3.0 deionized water 4.0 1520 toluene 2.4 912 *factor is
referenced to the amount of 4-nitrobenzaldehyde used
[0159] The methyl 3-hydroxy-2-methoxy-3-(4-nitrophenyl)propanoate
(I) in toluene solution in a stainless steel reactor was cooled to
0 to 10.degree. C. while flushing with nitrogen, and while
maintaining the temperature at 0 to 10.degree. C. triethylamine
(342 kg) and methanesulfonyl chloride (304 kg) were added, and the
reaction stirred at 0 to 10.degree. C. for 60 minutes. Deionized
water (1140 kg) was slowly added, and the resulting mass was
stirred at 55 to 60.degree. C. for 10 minutes, after which time
stirring was stopped and the phases were allowed to separate. The
aqueous phase was eliminated and the organic phase was filtered,
washing the filter with toluene (57 kg). The filtered solution was
heated to 55 to 60.degree. C. for 10 minutes. Stirring was stopped
and the phases were allowed to separate; the possible aqueous phase
was sent to the waste. Under vacuum and under stirring distil an
aliquot of the toluene taking into consideration the following
proportion: for 380 kg of nitrobenzaldehyde used in Scheme 15,
approximately 38 kg of toluene was distilled and this aliquot of
distilled toluene was sent to waste. The toluene was removed by
distillation under vacuum and without exceeding 60.degree. C., to
obtain an oily residue. The resulting residue was then treated with
methanol (1178 kg), flushed with nitrogen, cooled to 20 to
30.degree. C. and treated slowly with 30% sodium hydroxide (707
kg). The reaction was stirred at 20 to 30.degree. C. for 3 hours.
Deionized water (1474 kg) was added, and the solution heated to 60
to 65.degree. C. At this temperature, 37% hydrochloric acid (281
kg) and 85% phosphoric acid (61 kg) were slowly added to
precipitate the product. If necessary, 85% phosphoric acid was
added to obtain pH.ltoreq.3.0. The resulting precipitated product
was stirred at 60 to 65.degree. C. for at least 30 minutes then
cooled to 35 to 40.degree. C., and stirred for at least 30 minutes.
The mixture was centrifuged washing with deionized water (1520 kg)
and then washed with toluene (912 kg). The wet product (about 786
kg) was used in the next step.
Preparation of 3-(4-aminophenyl)-2-methoxypropanoic Acid (V):
##STR00046##
TABLE-US-00017 TABLE 16 Batch formula at production scale
(synthesis of compound (V)) Material Factor* Amount (kg)
2-methoxy-3-(4- nitrophenyl)acrylic 1.0 786 acid, wet methanol 3.0
1140 Ammonia 30% 0.3 114 deionized water 0.2 76 palladium on carbon
5% (containing 0.1 38 50% water) or palladium on carbon 5%
(recycled) deionized water 0.05 19 deionized water 0.05 19
deionized water 0.4 152 deionized water 2.0 760 hydrochloric acid
37% 0.32 122 acetic acid 80% 0.22 84 ethyl acetate 1.5 570
deionized water 1.0 380 ethyl acetate 1.0 380 *factor is referenced
to the amount of 4-nitrobenzaldehyde used
Preparation of Aqueous Suspension of Palladium at 5% on Carbon in
Water:
[0160] A suitable stainless steel reactor was loaded with deionized
water (76 kg), 5% palladium on carbon (38 kg) and then the bag was
washed with deionized water (19 kg).
Preparation of 3-(4-aminophenyl)-2-methoxypropanoic Acid (V):
[0161] A stainless steel reactor flushed with nitrogen (2.times.)
was loaded with wet 2-methoxy-3-(4-nitrophenyl)acrylic acid (IV)
(786 kg), methanol (1140 kg) and 30% ammonia (114 kg). After
restoring the atmospheric pressure, the mixture was stirred at 20
to 30.degree. C. up to complete dissolution. The resulting solution
was flushed with nitrogen (2.times.) and treated with a previously
prepared solution of 5% palladium on carbon in deionized water, and
the empty vessel was washed with deionized water (19 kg). The
reaction was flushed with nitrogen (2.times.), heated to 60 to
80.degree. C. then charged with hydrogen until a pressure of 4.0 to
4.5 atm was obtained. The reaction was allowed to proceed,
maintaining the pressure between 4.0 and 4.5 atm until hydrogen
consumption ceased and the reaction was confirmed complete. The
reactor was restored to atmospheric pressure and the reaction was
cooled to 20 to 30.degree. C., filtered through sparkler filter,
flushed with nitrogen (2.times.) and treated with deionized water
(152 kg) that was combined with the solution containing the
product. Without exceeding 50.degree. C., the solvent was distilled
under stirring and under vacuum up to oily residue. The residue was
treated with deionized water (760 kg), heated to 65 to 70.degree.
C. and the product precipitated by adding 37% hydrochloric acid
(122 kg) and 80% acetic acid (84 kg). The mixture was stirred at 65
to 70.degree. C. for at least 10 minutes; at this stage it was
confirmed that the pH was between 3.8 and 4.2 (not more than 4.2),
and then the mixture was treated with ethyl acetate (570 kg),
flushed with nitrogen and stirred at 65 to 70.degree. C. for at
least 15 minutes. The reaction mass was cooled to 15 to 20.degree.
C. and stirred for at least 30 minutes. The suspension was
centrifuged portion-wise washing with deionized water (380 kg) and
ethyl acetate (380 kg). The moist product was granulated, and dried
at 60 to 70.degree. C. to obtain
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (-295 kg).
Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic Acid
S-(+)-camphor-10-sulfonic Acid Salt:
##STR00047##
[0162] Starting material 3-(4-aminophenyl)-2-methoxypropanoic acid
deriving from two batches were combined (one entire batch and an
aliquot from a second one) to obtain the total amount of 400 kg of
3-(4-aminophenyl)-2-methoxypropanoic acid. This quantity is
equivalent to the amount that would have been obtained starting
from 500 kg of 4-nitrobenzaldehyde.
TABLE-US-00018 TABLE 17 Batch formula at production scale
(synthesis of compound (VI).cndot.(S)-CSA) Material Factor* Amount
(kg) 3-(4-aminophenyl)-2- 1.0 400 methoxypropanoic acid
(S)-(+)-10-camphor-sulfonic 1.2321 493 acetone 2.0 800 deionized
water 0.16 64 acetone 2.0 800 acetone 1.5 600 *factor is referenced
to the amount of 3-(4-aminophenyl)-2-methoxypropanoic acid (dried)
used
[0163] A stainless steel reactor was loaded with
3-(4-aminophenyl)-2-methoxypropanoic acid (V) (400 kg) and
(S)-(+)-camphor-10-sulfonic acid (493 kg); nitrogen was flushed and
acetone (800 kg) was added. Deionized water (64 kg) was added. The
reaction was heated to approximately 58.degree. C. for 1 hour
(reflux, dissolution does not occur). Acetone (800 kg) was added
(temperature approximately 58.degree. C.) and the reaction mass was
kept at reflux (approx. 58.degree. C.) for 1 hour; the reaction
mass was then cooled to 37 to 42.degree. C. and was centrifuged
portion-wise washing with acetone (600 kg) (between every
centrifugation step, the suspension aliquot that was not involved
in the centrifugation was first heated tan kept at 45 to 50.degree.
C. and then, before the subsequent centrifugation, the suspension
was cooled again to 37 to 42.degree. C.). The centrifuged product
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (wet weight: 470
kg, 409.7 as dried) was used directly in the next step.
Preparation of (S)-(-)-3-(4-Aminophenyl)-2-methoxypropionic acid
(VI):
##STR00048##
TABLE-US-00019 TABLE 18 Batch formula at production scale
(synthesis of compound (VI)) Material Factor* Amount (kg) deionized
water 2.0 819 (S)-(-)-3-(4-Aminophenyl)-2- 1.0 470 (409.7
methoxypropionic acid S-(+)- kg as dried) camphor-10-sulfonic acid
salt, wet deionized water 0.2 82 ethyl acetate 1.0 410 ammonia 30%
0.1257 51 acetic acid 80% 0.05 20.5 deionized water 0.7 287 ethyl
acetate 0.7 287 *factor is referenced to the amount of
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid S-
(+)-camphor-10-sulfonic acid salt used (as dried).
[0164] A stainless steel reactor was charged with deionized water
(819 kg) and wet ((S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
S-(+)-camphor-10-sulfonic acid salt (VI) (S)-CSA (wet weight: 470
kg, 409.7 as dried), flushed with nitrogen and heated for at least
10 minutes at 20 to 40.degree. C. until complete dissolution
occurred. The solution was filtered washing with deionized water
(82 kg), then ethyl acetate (410 kg). The resulting solution was
flushed with nitrogen, heated to 55 to 60.degree. C. and 30%
ammonia (51 kg) was added to precipitate the product. The resulting
mixture was stirred for at least 15 minutes at 55 to 60.degree. C.
then 80% acetic acid (20.5 kg) was added through a filter and the
reaction flushed with nitrogen and stirred at 55 to 60.degree. C.
for at least 30 minutes then cooled down to 2-7.degree. C. and
stirred for at least 1 hour. The reaction mass was centrifuged
portion-wise and washed with deionized water (287 kg), ethyl
acetate (287 kg) to deliver wet
(S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (VI) (wet weight
162 kg, 138.8 kg as dried), which was used (wet) directly in the
next step.
Preparation of (S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic
Acid (VII):
##STR00049##
TABLE-US-00020 TABLE 19 Batch formula at production scale
(synthesis of compound (VII)) Material Factor* Amount (kg) Wet
(S)-(-)-3-(4-Aminophenyl)- 1.0 162 (138.8 2- methoxypropionic acid
kg as dried) ethyl acetate 1.5 208 acetic anhydride 0.65 90 ethyl
acetate 0.5 4.80 deionized water 1.5 208 *factor is referenced to
the amount of (S)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
used (as dried)
[0165] A stainless steel reactor was charged with wet
(S)-3-(4-aminophenyl)-2-methoxypropanoic acid (VI) (wet weight 162
kg, 138.8 kg as dried) and ethyl acetate (208 kg), under nitrogen.
The mixture was heated to 65 to 70.degree. C. and acetic anhydride
(90 kg) was added through a cartridge filter over about 15 minutes.
The reaction was stirred at 65 to 70.degree. C. for 90 minutes and,
once the reaction end was detected, continuously stirred until
formation of a precipitate. The mixture was cooled to 10 to
20.degree. C. and stirred at 10 to 20.degree. C. for 30 minutes,
then centrifuged and the resulting solid washed with ethyl acetate
(69 kg), and deionized water (208 kg). The resulting product was
dried at 60 to 70.degree. C. for 19 hours, and milled to obtain
(S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid (VII) (154.5
kg).
[0166] (S)-(-)-3-(4-Acetamidophenyl)-2-methoxypropionic acid (VII):
IR: 3319, 2888, 2825, 1718, 1633, 1599, 1548, 1107 cm.sup.-1; LCMS
(+)ESI: m/z calculated for C.sub.12H.sub.15N.sub.4: 237, found 236
(M-H).sup.-; .sup.1E1 NMR (600 MHz, DMSO-d.sub.6): .delta. 12.70
(s, 1 H), 9.85 (s, 1 H), 7.45 (d, 2 H), 7.12 (d, 2 H), 3.90 (dd, 1
H), 3.20 (s, 3 H), 2.80 (ABd, 2 H), 2.00 (s, 3 H). .sup.13C NMR
(600 MHz, DMSO-d.sub.6): .delta. 24.09 (CH.sub.3--CO--NH--), 37.94
(--C--CH.sub.2--C--), 57.47 (CH.sub.3--O--), 80.98
(--C--CH(O)--C--), 119.25 (2C, aromatic), 129.65 (2C, aromatic),
132.24 (1C, aromatic), 137.87 (1C, aromatic), 168.47
(CH.sub.3--CO--NH--), 173.21 (--COOH). EA: C 60.82% (theor.
60.75%), H 6.44% (theor. 6.37%), N 5.91% (theor. 5.90%), 0 26.97%
(theor. 26.97%). DSC: melting 154-167.degree. C. (onset 159.degree.
C.). Specific optical rotation: -22.7.
(S)-3-(4-aminophenyl)-2-methoxypropanoic acid (HPLC): 0.06% (HPLC).
Chiral purity (HPLC): 99.7% (HPLC). Residual solvents (ethyl
acetate): 277 ppm (GC).
Example 7: X-Ray Crystal Structure Determination of Compound of
Formula (VII)
[0167] The crystal used in the structural determination was
obtained by vapour diffusion of a solution of compound of Formula
(VII) and L-proline (2:1) in ethanol, using heptane as antisolvent.
Single crystal X-ray diffraction analysis was performed. The
results of this analysis are shown below. Refinement on the
P2.sub.12.sub.12.sub.1 space group lead to an R index of 0.062. The
asymmetric unit is composed by two compound of Formula (VII) and
two L-proline molecules.
[0168] Analysis of the single crystal diffraction data shows that
the absolute configuration of the carbon alpha to the carboxylic
acid group is (S). Based on these results, the absolute
stereochemistry of the compound of Formula (VII) is shown in the
structure below.
##STR00050##
[0169] The optical rotation of the same compound, i.e., the
compound of Formula (VII), is negative, which means is turns
plane-polarized light to the left. The specification of the
specific rotation for the pure compound is -26.0.degree. to
-19.0.degree. . Accordingly, because the procedure for resolving
the racemic mixture always employs the same reagents,
characterization that the product obtained has the (S)
configuration is confirmed by specific optical rotation.
[0170] In addition, the chiral purity (HPLC) of the compound of
Formula (VII) can be determined, for example using the method
described herein.
[0171] The crystal data and structure refinement for the single
crystal X-ray diffraction of the compound of Formula
(VII):L-proline derivative is set out below.
TABLE-US-00021 Empirical formula C.sub.17H.sub.24N.sub.2O.sub.6
Formula weight 352.38 Temperature 296(2) K Diffractometer Bruker
Smart-Apex (area detector) Wavelength 0.71073 .ANG. Crystal system
Orthorhombic Space group P2.sub.12.sub.12.sub.1 Unit cell
dimensions a = 7.7813(5) .ANG. a = 90.degree. b = 9.5414(6) .ANG.
.beta. = 90.degree. c = 49.006(3) .ANG. .gamma. = 90.degree. Volume
3638.4(4) .ANG..sup.3 Z 8 Density (calculated) 1.287 Mg/m.sup.3
Absorption coefficient 0.098 mm.sup.-1 F(000) 1504 Crystal size
0.49 .times. 0.25 .times. 0.08 mm.sup.3 Theta range for data
collection 0.83 to 28.75.degree.. Index ranges -10 <= h <= 8,
-12 <= k <= 12, -54 <= l <= 63 Reflections collected
19513 Independent reflections 8598 [R(int) = 0.0437] Completeness
to theta = 25.00.degree. 99.7% Absorption correction Semi-empirical
from equivalents Max. and min transmission 0.992 and 0.777
Refinement method Full-matrix least-squares on F.sup.2
Data/restraints/parameters 8598/0/474 Goodness-of-fit on F.sup.2
0.984 Final R indices [I > 2sigma(I)] R1 = 0.0623, wR2 = 0.1517
R indices (all data) R1 = 0.1217, wR2 = 0.1843 Absolute structure
parameter -0.8(13) Largest diff. peak and hole 0.382 and -0307
e..ANG..sup.-3 Computing programs (Bruker) Smart 5.6/Saint
5.0/Shelxtl-NT 6.1
INCORPORATION BY REFERENCE
[0172] All publications and patents mentioned herein, including
those items listed below, are hereby incorporated by reference in
their entirety for all purposes as if each individual publication
or patent was specifically and individually incorporated by
reference. In case of conflict, the present application, including
any definitions herein, will control.
EQUIVALENTS
[0173] While specific embodiments of the subject disclosure have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the disclosure will become apparent
to those skilled in the art upon review of this specification. The
full scope of the disclosure should be determined by reference to
the claims, along with their full scope of equivalents, and the
specification, along with such variations.
[0174] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
this specification and attached claims are approximations that may
vary depending upon the desired properties sought to be obtained by
the present disclosure.
* * * * *